U.S. patent number 5,700,839 [Application Number 08/546,570] was granted by the patent office on 1997-12-23 for alkyl-5-methylsulfonylbenzoylguanidine derivatives.
This patent grant is currently assigned to Merck Patent Gesellschaft mit Beschrankter Haftung. Invention is credited to Manfred Baumgarth, Norbert Beier, Dieter Dorsch, Rolf Gericke, Klaus-Otto Minck.
United States Patent |
5,700,839 |
Gericke , et al. |
December 23, 1997 |
Alkyl-5-methylsulfonylbenzoylguanidine derivatives
Abstract
Benzoylguanidines of the formula I ##STR1## wherein R.sup.1 and
R.sup.2 have the meanings indicated herein, and their
physiologically acceptable salts, show anti-arrhythmic properties
and act as inhibitors of the cellular NA.sup.+ /H.sup.+
antiporter.
Inventors: |
Gericke; Rolf (Seeheim,
DE), Dorsch; Dieter (Ober-Ramstadt, DE),
Baumgarth; Manfred (Darmstadt, DE), Minck;
Klaus-Otto (Ober-Ramstadt, DE), Beier; Norbert
(Reinheim, DE) |
Assignee: |
Merck Patent Gesellschaft mit
Beschrankter Haftung (Darmstadt, DE)
|
Family
ID: |
6531500 |
Appl.
No.: |
08/546,570 |
Filed: |
October 20, 1995 |
Foreign Application Priority Data
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Oct 22, 1994 [DE] |
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44 37 874.2 |
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Current U.S.
Class: |
514/618; 514/821;
564/139; 564/144; 514/866; 564/133; 564/162 |
Current CPC
Class: |
A61P
9/06 (20180101); C07C 317/44 (20130101); A61P
9/10 (20180101); A61P 9/08 (20180101); A61P
9/00 (20180101); Y10S 514/821 (20130101); Y10S
514/866 (20130101) |
Current International
Class: |
C07C
317/00 (20060101); C07C 317/44 (20060101); A61K
031/165 (); C07C 235/50 (); C07C 231/02 (); C07C
231/12 () |
Field of
Search: |
;514/618,821,866
;564/162,133,139,144 |
Foreign Patent Documents
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0416499 |
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Mar 1991 |
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EP |
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0556673 |
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Aug 1993 |
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EP |
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Primary Examiner: O'Sullivan; Peter
Attorney, Agent or Firm: Millen, White, Zelano, &
Branigan, P.C.
Claims
We claim:
1. A benzoylguanidine compound of the formula I ##STR5## wherein
R.sup.1 is methyl or ethyl and
R.sup.2 is H, a straight-chain or branched C.sub.1 -C.sub.6 -alkyl-
or C.sub.2 -C.sub.6 -alkenyl-radical, C.sub.3 -C.sub.7 -cycloalkyl,
benzyl or phenyl which is unsubstituted or mono-, di- or
trisubstituted by methyl, methoxy, amino, F, Cl, Br or
CF.sub.3,
and their physiologically acceptable salts.
2. The compound:
(a)
N-diaminomethylene-2-methyl-4-phenoxy-5-methylsulfonylbenzamide;
(b)
N-diaminomethylene-2-ethyl-4-methoxy-5-methylsulfonylbenzamide;
(c)
N-diaminomethylene-2-methyl-4-ethoxy-5-methylsulfonylbenzamide;
(d)
N-diaminomethylene-2-methyl-4-(2-chloro-phenoxy)-5-methylsulfonylbenzamide
; or
(e)
N-diaminomethylene-2-methyl-4-(4-chloro-phenoxy)-5-methylsulfonylbenzamide
;
according to claim 1, or physiologically acceptable salts
thereof.
3. A process for the preparation of the benzoylguanidine compounds
of the formula I according to claim 1, and also their salts, which
comprises reacting a compound of the formula II ##STR6## wherein
R.sup.1 and R.sup.2 have the meanings indicated above, Q is Cl, Br,
OA, O--CO--A, --O--CO--Ph, OH or another reactive esterified OH
group or leaving group which can be easily nucleophilically
substituted and
A is alkyl having 1-6 C atoms,
with guanidine, or comprising reacting a benzoylguanidine of the
formula III ##STR7## wherein R.sup.1 has the meanings indicated
above, and X is F, Cl, Br, I or another suitable leaving group,
with an alcohol or phenol of the formula IV
wherein R.sup.2 has the meaning indicated, optionally after prior
conversion to an alkoxide,
or comprising reacting a phenol of the formula I wherein R.sup.2 =H
and R.sup.1 has the meaning indicated with a compound of the
formula R.sup.2 --X wherein R.sup.2 and X have the meanings
indicated,
or which comprises treating a compound which otherwise corresponds
to the formula I, but which instead of one or more hydrogen atoms
contains one or more reducible groups and/or one or more additional
C-C and/or C-N bonds, with a reducing agent,
or which comprises treating a compound which otherwise corresponds
to the formula I, but which instead of one or more hydrogen atoms
contains one or more solvolysable groups, with a solvolysing agent,
or which comprises converting a base of the formula I into one of
its salts by treating with an acid.
4. A process for the production of a pharmaceutical preparation,
wherein a compound of the formula I according to claim 1 and/or one
of its physiologically acceptable salts is brought into a suitable
dose form together with at least one solid, liquid or semi-liquid
excipient or auxiliary.
5. A pharmaceutical preparation, comprising at least one compound
of the formula I according to claim 1 and/or one of its
physiologically acceptable salts and a pharmaceutically acceptable
carrier.
6. The compound of claim 1, wherein R.sup.2 is methyl, ethyl,
unsubstituted phenyl, phenyl monosubstituted by fluorine or
chlorine, benzyl or cycloalkyl of 3, 5 or 6 carbon atoms.
7. A method for the treatment or preventive treatment of
arrhythmias, angina pectoris and infarcts which comprises
administering to a subject in need thereof a disease controlling
effective amount of a compound of the formula I of claim 1 or a
physiologically acceptable salt thereof.
8. A method for treating or preventing an illness indicated by
activity of the cellular Na.sup.+ /H.sup.+ antiporter which
comprises administering to a patient a cellular Na.sup.+ /H.sup.+
antiporter inhibiting effective amount of a compound according to
formula I of claim 1 and/or one of its physiologically acceptable
salts.
9. The method of claim 8, wherein the illness is cardiac
arrhythmia, infarct, angina pectoris, an ischaemia of the nervous
system, shock, hypertension, arteriosclerosis, diabetic late
complications, oncoses, a fibrotic disorder or an organ hypertrophy
or hyperplasia.
10. A method for inducing a cellular Na.sup.+ /H.sup.+ antiporter
inhibiting effect in a patient which comprises administering to the
patient a cellular Na.sup.+ /H.sup.+ antiporter inhibiting
effective amount of a compound according to formula I of claim 1
and/or one of its physiologically acceptable salts.
11. A compound according to claim 1, wherein R.sup.1 is methyl.
Description
The invention relates to benzoylguanidine derivatives of the
formula I ##STR2## wherein R.sup.1 is methyl or ethyl and
R.sup.2 is H, a straight-chain or branched C.sub.1 -C.sub.6 -alkyl-
or C.sub.2 -C.sub.6 -alkenyl-radical, C.sub.3 -C.sub.7 -cycloalkyl,
benzyl or phenyl which is unsubstituted or mono-, di- or
trisubstituted by methyl, methoxy, amino, F, Cl, Br and/or
CF.sub.3,
and their physiologically acceptable salts.
An object of the invention is finding novel compounds having useful
properties, in particular those which can be used for the
production of medicaments.
Upon further study of the specification and appended claims,
further objects and advantages of this invention will become
apparent to those skilled in the art.
It has been found that the compounds of the formula I and their
physiologically acceptable salts have useful pharmacological
properties combined with good tolerability.
The novel compounds are inhibitors of the cellular Na.sup.+
/H.sup.+ antiporter, i.e., active compounds which inhibit the
Na.sup.+ /H.sup.+ exchange mechanism of the cells (Dusing et al.,
Med. Klin. 87, 378-384 (1992)) and are thus good antiarrythmics.
They are particularly suitable for the treatment of arrhythmias
which occur as a result of oxygen deficiency.
The best known active compound of the acylguanidine group is
amiloride. This substance, however, primarily shows a hypotensive
and saluretic action, which is undesired, in particular in the
treatment of cardiac arrhythmias, while the antiarrhythmic
properties are only very poorly pronounced.
Moreover, structurally similar compounds are known, for example,
from EP 04 16 499.
The invention relates to compounds of the formula I and their
physiologically acceptable salts.
The substances according to the invention of the present
application show a good cardioprotective action and are therefore
particularly suitable for infarct treatment, infarct prophylaxis
and for the treatment of angina pectoris. The substances also
counteract all pathological hypoxic and ischaemic damage, so that
the diseases caused primarily or secondarily thereby can be
treated. The active compounds are also highly suitable for
preventive applications.
On account of the protective effects of these substances in
pathological hypoxic or ischaemic situations, other application
possibilities result therefrom in surgical interventions for the
protection of temporarily undersupplied organs, in organ
transplantation for the protection of the removed organs, in
angioplastic vascular or cardiac interventions, in ischaemias of
the nervous system, in the therapy of states of shock and for the
preventive treatment of essential hypertension.
In addition, the compounds can also be used as therapeutics in
disorders caused by cell proliferation, such as arteriosclerosis,
diabetic late complications, oncoses, fibrotic disorders, in
particular of the lungs, liver and kidneys, as well as organ
hypertrophies and hyperplasias. The substances are moreover
suitable for diagnostic application for the identification of
diseases which are accompanied by an increased activity of the
Na.sup.+ /H.sup.+ antiporter, e.g. in erythrocytes, platelets or
leukocytes.
The effects of the compounds can be determined with the aid of
methods known per se, such as are indicated by N. Escobales and J.
Figueroa in J. Membrane Biol. 120, 41-49 (1991) or by L. Counillon,
W. Scholz, H. J. Lang and J. Pouyssegur in Mol. Pharmacol. 44,
1041-1045 (1993).
Suitable experimental animals are, for example, mice, rats,
guinea-pigs, dogs, cats, monkeys or pigs.
The compounds can therefore be used as pharmaceutically active
compounds in human and veterinary medicine. They can also be used
as intermediates for the production of other pharmaceutically
active compounds.
R.sup.2 is preferably methyl, ethyl or phenyl, but also preferably
benzyl or cycloalkyl having 3, 5 or 6 C atoms, i.e. in particular
cyclopropyl, cyclopentyl or cyclohexyl. If R.sup.2 is phenyl, it is
preferably unsubstituted or monosubstituted by fluorine or
chlorine.
Accordingly, the invention in particular relates to those compounds
of the formula I in which at least one of the radicals mentioned
has one of the preferred meanings indicated above. Some preferred
compounds of the formula I are:
N-diaminomethylene-2-methyl-4-phenoxy-5-methylsulfonylbenzamide;
N-diaminomethylene-2-ethyl-4-phenoxy-5-methylsulfonylbenzamide;
N-diaminomethylene-2-methyl-4-hydroxy-5-methylsulfonylbenzamide;
N-diaminomethylene-2-ethyl-4-hydroxy-5-methylsulfonylbenzamide;
N-diaminomethylene-2-methyl-4-benzyloxy-5-methylsulfonylbenzamide;
N-diaminomethylene-2-ethyl-4-benzyloxy-5-methylsulfonylbenzamide;
N-diaminomethylene-2-methyl-4-methoxy-5-methylsulfonylbenzamide;
N-diaminomethylene-2-ethyl-4-methoxy-5-methylsulfonylbenzamide;
N-diaminomethylene-2-ethyl-4-cyclopropyloxy-5-methylsulfonylbenzamide;
N-diaminomethylene-2-ethyl-4-cyclopentyloxy-5-methylsulfonylbenzamide;
N-diaminomethylene-2-ethyl-4-cyclohexyloxy-5-methylsulfonylbenzamide.
The invention also relates to a process for preparing the compounds
of the formula I according to claim 1, and also their salts,
characterized in that a compound of the formula II ##STR3## wherein
R.sup.1 and R.sup.2 have the meanings indicated above and Q is Cl,
Br, OA, O--CO--A, O--CO--Ph, OH or another reactive esterified OH
group or leaving group which can be easily nucleophilically
substituted and
A is alkyl having 1-6 C atoms, is reacted with guanidine, or in
that a benzoylguanidine of the formula III ##STR4## wherein R.sup.1
has the meanings indicated above, and X is F, Cl, Br, I or another
suitable leaving group, is reacted with an alcohol or phenol of the
formula IV
wherein
R.sup.2 has the meaning indicated,
if appropriate after prior conversion to an alkoxide,
or in that an alcohol (phenol) of the formula I wherein R.sup.2 =H
and R.sup.1 has the meaning indicated is reacted with a compound of
the formula R.sup.2 -X wherein R.sup.2 and X have the meanings
indicated,
or in that a compound which otherwise corresponds to the formula I,
but which instead of one or more hydrogen atoms contains one or
more reducible groups and/or one or more additional C-C and/or C-N
bonds, is treated with a reducing agent,
or in that a compound which otherwise corresponds to the formula I,
but which instead of one or more hydrogen atoms contains one or
more solvolysable groups, is treated with a solvolysing agent
and/or in that a base of the formula I which is obtained is
converted into one of its salts by treating with an acid.
The compounds of the formula I are otherwise prepared by methods
known per se, as are described in the literature (e.g. in the
standard works such as Houben-Weyl, Methoden der organischen Chemie
(Methods of organic chemistry), Georg-Thieme-Verlag, Stuttgart;
Organic Reactions, John Wiley & Sons, Inc., New York; and in
the patent application indicated above), namely under reaction
conditions which are known and suitable for the reactions
mentioned. In this case, use can also be made of variants which are
known per se but are not mentioned in greater detail here.
If desired, the starting substances can also be formed in situ in
such a way that they are not isolated from the reaction mixture,
but immediately reacted further to give the compounds of the
formula I.
Preferably, compounds of the formula I are prepared by reacting an
activated carboxylic acid derivative of the formula II, where Q is
particularly preferably Cl or --O--CH.sub.3, with guanidine.
Particularly suitable reaction variants are also those in which the
free carboxylic acid II (Q=OH) is reacted in a manner known per se
to give the respective activated derivative and this is then
reacted directly, without intermediate isolation, with guanidine.
Methods in which intermediate isolation is unnecessary are, for
example, activation with carbonyldiimidazole,
dicyclohexylcarbodiimide or the Mukayama variant (Angew. Chem. 91,
788-812 (1979)).
Generally, the carboxylic acids and carboxylic acid derivatives of
the formula II are known. They are prepared, in particular, by
reacting an appropriate 2-alkyl-4-halo-5-methylsulfonylbenzoic acid
derivative with an alkoxide or a phenoxide which can be derived
from an alcohol or phenol of the formula IV.
The reaction is carried out in analogy to the reaction of the
compounds III and IV. It is described below.
The reaction of a reactive carboxylic acid derivative of the
formula II with guanidine is carried out in a manner known per se,
preferably in a protic or aprotic polar or non-polar inert organic
solvent.
Suitable solvents for the reaction of the compounds III and IV are
mentioned below. Particularly preferred solvents are, however,
methanol, THF, dimethoxyethane, dioxane or mixtures which can be
prepared therefrom, as well as water. Suitable reaction
temperatures are, for example, temperatures from 20.degree. C. to
the boiling point of the solvent. The reaction times are preferably
from 5 minutes to 12 hours. It is expedient to employ an acid
scavenger in the reaction. Those suitable for this purpose are any
types of bases which do not interfere with the reaction itself.
Particularly suitable, however, is the use of inorganic bases such
as potassium carbonate or of organic bases such as triethylamine or
pyridine or else an excess of the guanidine.
Compounds of the formula I can also be prepared by reacting a
benzoylguanidine of the formula III with a compound of the formula
IV. The starting substances of the formula III can be prepared by
reaction of appropriately substituted benzoic acids or reactive
acid derivatives which can be derived therefrom, such as acid
halides, esters or anhydrides, with guanidine under reaction
conditions as are known per se and generally customary for amide
preparation. Particularly suitable reaction variants are, in turn,
those as have previously been indicated for the reaction of
compound II with guanidine.
The preparation of the compound II and the reaction of the compound
III with a compound of the formula IV are carried out in a manner
known per se, preferably in a protic or aprotic polar inert organic
solvent.
In the preparation of II or in the reaction of III with IV, it is
also expedient to work in the presence of a base or with an excess
of the basic component. Suitable bases are preferably, for example,
alkali metal or alkaline earth metal hydroxides, carbonates or
alkoxides, or organic bases such as triethylamine or pyridine which
are also used in an excess and can then simultaneously serve as
solvents.
Suitable inert solvents are particularly alcohols such as methanol,
ethanol, isopropanol, n-butanol or tert-butanol; ethers such as
diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;
glycol ethers such as ethylene glycol monomethyl ether or monoethyl
ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl
ether (diglyme); ketones such as acetone or butanone; nitriles such
as acetonitrile; nitro compounds such as nitromethane or
nitrobenzene; esters such as ethyl acetate; amides such as
hexamethylphosphoramide; sulfoxides such as dimethyl sulfoxide
(DMSO); chlorinated hydrocarbons such as dichloromethane,
chloroform, trichloroethylene, 1,2-dichloroethane or carbon
tetrachloride; or hydrocarbons such as benzene, toluene or xylene.
Mixtures of these solvents with one another are additionally
suitable.
The compounds of the formula I can also be obtained by setting them
free from their functional derivatives by solvolysis, in particular
hydrolysis, or by hydrogenolysis.
Preferred starting substances for the solvolysis or hydrogenolysis
are those which otherwise correspond to the formula I, but instead
of one or more free amino and/or hydroxyl groups contain
corresponding protected amino and/or hydroxyl groups, preferably
those which, instead of an H atom which is bonded to an N atom,
carry an amino protective group, in particular those which instead
of an HN group carry an R'-N group wherein R' is an amino
protective group, and/or those which instead of the H atom of a
hydroxyl group carry a hydroxyl protective group, e.g. those which
correspond to the formula I but instead of an OH group carry an OR"
group wherein R" is a hydroxyl protective group.
Two or more identical or different protected amino and/or hydroxyl
groups can also be present in the molecule of the starting
substance. If the protective groups present are different from one
another, in many cases they can be removed selectively.
The expression "amino protective group" is generally known and
relates to groups which are suitable for protecting (for blocking)
an amino group from chemical reactions, but which are easily
removable after the desired chemical reaction has been carried out
in another position of the molecule. Typical groups of this type
are particularly unsubstituted or substituted acyl, aryl (e.g.
2,4-dinitrophenyl (DNP)), aralkoxymethyl (e.g. benzyloxymethyl
(BOM)) or aralkyl groups (e.g. benzyl, 4-nitrobenzyl,
triphenylmethyl). As the amino protective groups are removed after
the desired reaction (or reaction sequence) their nature and size
is otherwise uncritical; however those having 1-20, in particular
1-8, C atoms are preferred. The expression "acyl group" is to be
interpreted in the widest sense in connection with the present
process. It includes acyl groups derived from aliphatic,
araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic
acids and also, in particular, alkoxycarbonyl, aryloxycarbonyl and
especially aralkoxycarbonyl groups. Examples of acyl groups of this
type are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl
such as phenylacetyl; aroyl such as benzoyl or tolyl;
aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as
methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,
isopropoxycarbonyl, tert-butoxycarbonyl (BOC),
2-iodoethoxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl
(CBZ), 4-methoxybenzyloxycarbonyl and 9-fluorenylmethoxycarbonyl
(FMOC). Preferred amino protective groups are BOC, DNP and BOM, and
also CBZ, benzyl and acetyl.
The expression "hydroxyl protective group" is also generally known
and relates to groups which are suitable for protecting a hydroxyl
group from chemical reactions, but which are easily removable after
the desired chemical reaction has been carried out in another
position of the molecule. Typical groups of this type are the
abovementioned unsubstituted or substituted aryl, aralkyl or acyl
groups, and also alkyl groups. The nature and size of the hydroxyl
protective groups is not critical, as they are removed after the
desired chemical reaction or reaction sequence; groups having 1-20,
in particular 1-10, C atoms are preferred. Examples of hydroxyl
protective groups are, inter alia, tert-butyl, benzyl,
p-nitrobenzoyl, p-toluenesulfonyl and acetyl, benzyl and acetyl
being particularly preferred.
The functional derivatives of the compounds of the formula I to be
used as starting substances can be prepared by customary methods,
as are described, for example, in the standard works and patent
applications mentioned, e.g. by reaction of compounds which
correspond to the formulae II and III, but where at least one of
these compounds contains a protective group instead of an H
atom.
The liberation of the compounds of the formula I from their
functional derivatives takes place, depending on the protective
group used, e.g. with strong acids, expediently with
trifluoroacetic acid or perchloric acid, but also with other strong
inorganic acids such as hydrochloric acid or sulfuric acid, strong
organic carboxylic acids such as trichloroacetic acid, or sulfonic
acids such as benzene- or p-toluenesulfonic acid. The presence of
an additional inert solvent is possible, but not always
necessary.
Suitable inert solvents are preferably organic, for example
carboxylic, acids such as acetic acid, ethers such as
tetrahydrofuran (THF) or dioxane, amides such as dimethylformamide
(DMF), halogenated hydrocarbons such as dichloromethane, and also
alcohols such as methanol, ethanol or isopropanol, and also water.
Mixtures of the abovementioned solvents are also possible.
Trifluoroacetic acid is preferably used in an excess without
addition of a further solvent; perchloric acid is used in the form
of a mixture of acetic acid and 70% perchloric acid in the ratio
9:1. The reaction temperatures for the cleavage are expediently
from approximately 0.degree. C. to approximately 50.degree. C.; the
reaction is preferably carried out at about from
15.degree.-30.degree. C. (room temperature).
The BOC group can be preferably removed, for example, using 40%
trifluoroacetic acid in dichloromethane or using approximately. 3
to 5N HCl in dioxane at 15.degree.-60.degree. C.; the FMOC group
using an approximately 5-20% solution of dimethylamine,
diethylamine or piperidine in DMF at 15.degree.-50.degree. C.
Removal of the DNP group is carried out, for example, also using an
approximately 3-10% solution of 2-mercaptoethanol in DMF/water at
15.degree.-30.degree. C.
Hydrogenolytically removable protective groups (e.g. BOM, CBZ or
benzyl) can be removed, for example, by treating with hydrogen in
the presence of a catalyst (e.g. a noble metal catalyst such as
palladium, expediently on a support such as carbon). Suitable
solvents in this case are those indicated above, in particular, for
example, alcohols such as methanol or ethanol or amides such as
DMF. Generally, the hydrogenolysis is carried out at temperatures
from approximately 0.degree.-100.degree. C. and pressures from
approximately 1-200 bar, preferably at 20.degree.-30.degree. C. and
1-10 bar. Hydrogenolysis of the CBZ group takes place readily, for
example, on 5-10% Pd-C in methanol at 20.degree.-30.degree. C.
A base of the formula I can also be converted into the associated
acid addition salt using an acid. For this reaction, possible acids
are those which give physiologically acceptable salts. Inorganic
acids can thus be used, e.g. sulfuric acid, nitric acid, halohydric
acids such as hydrochloric acid or hydrobromic acid, phosphoric
acids such as orthophosphoric acid, sulfamic acid, and also organic
acids, in particular aliphatic, alicyclic, araliphatic, aromatic or
heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric
acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid,
diethylacetic acid, malonic acid, succinic acid, pimelic acid,
fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid,
benzoic acid, salicylic acid, 2- or 3-phenyl-propionic acid, citric
acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic
acid, methane- or ethanesulfonic acid, ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, naphthalenemono- and disulfonic acids and
laurylsuifuric acid.
The compounds may be used as pharmaceutical agents in a manner
analogous to amiloride and other known acylguanidine compounds, but
exhibiting the advantages described herein, e.g. inhibition of the
cellular Na.sup.+ /H.sup.+ exchange mechanism and activity in the
treatment and prevention of disturbances of the cardiac rhythm. As
intermediates, the compounds may be used to prepare
pharmaceutically active compounds using synthetic methods analogous
to those known in the art.
The compounds of the formula I and their physiologically acceptable
salts can be used for the production of pharmaceutical
preparations, in particular by non-chemical routes. In this
context, they can be brought into a suitable dose form together
with at least one solid, liquid and/or semi-liquid excipient or
auxiliary and, if appropriate, in combination with one or more
other active compounds.
The invention also relates to compositions, in particular
pharmaceutical preparations, containing at least one compound of
the formula I and/or one of its physiologically acceptable
salts.
These preparations can be used as medicaments in human or
veterinary medicine. Possible excipients are organic or inorganic
substances which are suitable for enteral (e.g. oral) or parenteral
administration or topical application and do not react with the
novel compounds, for example water, vegetable oils, benzyl
alcohols, polyethylene glycols, glycerol triacetate, gelatin,
carbohydrates such as lactose or starch, magnesium stearate, talc,
lanolin and petroleum jelly. Tablets, coated tablets, capsules,
syrups, juices or drops, in particular, are used for oral
administration, suppositories for rectal administration, solutions,
preferably oily or aqueous solutions, and also suspensions,
emulsions or implants, for parenteral administration, and
ointments, creams, pastes, lotions, gels, sprays, foams, aerosols,
solutions (e.g. solutions in alcohols such as ethanol or
isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol
or mixtures thereof with one another and/or with water) or powders
for topical application. The novel compounds can also be
lyophilized and the lyophilizates obtained used, for example, for
the production of injection preparations.
Liposomal preparations are also suitable, in particular for topical
application. The preparations indicated can be sterilized and/or
contain auxiliaries such as lubricants, preservatives, stabilizers
and/or wetting agents, emulsifiers, salts for affecting the osmotic
pressure, buffer substances, colorants, flavorings and/or aromatic
substances. If desired, they can also contain one or more other
active compounds, e.g. one or more vitamins.
The compounds of the formula I and their physiologically acceptable
salts can be administered to humans or animals, in particular
mammals such as monkeys, dogs, cats, rats or mice, and used in the
therapeutic treatment of the human or animal body and also in the
control of diseases, in particular in the therapy and/or
prophylaxis of disorders of the cardiovascular system. They are
therefore suitable for the treatment of arrhythmias, in particular
if these are caused by oxygen deficiency, of angina pectoris,
infarcts, ischaemias of the nervous system such as, for example,
stroke or cerebral oedema, of states of shock and for preventive
treatment, for example, preventive treatment of the above
disorders.
The substances can also be employed as therapeutics in disorders in
which cell proliferation plays a role, such as arteriosclerosis,
diabetic late complications, oncoses, fibroses and organ
hypertrophies and hyperplasias, in particular in disorders of the
prostate.
In this case, generally, the substances according to the invention
are administered in analogy to known antiarrhythmics, e.g.
aprindine, preferably in doses from approximately 0.01-5 mg, in
particular from 0.02-0.5 mg per unit dose. The daily dose is
preferably from approximately 0.0001-0.1, in particular from
0.0003-0.01, mg/kg of body weight. The specific dose for each
intended patient, however, depends on all sorts of factors, for
example on the efficacy of the specific compound employed, on the
age, body weight, the general state of health, sex, on the diet, on
the time and route of administration, and on the excretion rate,
pharmaceutical combination and severity of the particular disorder
to which the therapy applies. Oral administration is preferred.
Without further elaboration, it is believed that one skilled in the
art can, using the preceding description, utilize the present
invention to its fullest extent. The following preferred specific
embodiments are, therefore, to be construed as merely illustrative,
and not limitative of the remainder of the disclosure in any way
whatsoever.
In the foregoing and in the following examples, all temperatures
are set forth uncorrected in degrees Celsius and unless otherwise
indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and
publications, cited above and below, and of the corresponding
application, German Application P4437874.02, are hereby
incorporated by reference.
In the following examples "customary working up" means:
If necessary, water is added, the mixture is extracted with an
organic solvent such as ethyl acetate, the organic phase is
separated off, dried over sodium sulfate, filtered and evaporated
and the residue is purified by chromatography and/or
crystallization.
EXAMPLE 1
A solution of 1.4 g of methyl
2-methyl-4-ethoxy-5-methylsulfonylbenzoate (obtainable by reaction
of 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with sodium
ethoxide and subsequent esterification) and 1.5 g of guanidine in
50 ml of methanol is boiled for five hours and the solvent is then
removed. The residue is treated with water, and the crystallizate
which remains is filtered off with suction and treated with dilute
sodium hydroxide solution. The solid residue is filtered off and
recrystallized from ethanol, and
N-diaminomethylene-2-methyl-4-ethoxy-5-methylsulfonylbenzamide is
obtained, m.p. 201.degree.-203.degree..
Analogously, reaction of guanidine
with methyl 2-ethyl-4-ethoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-ethoxy-5-methylsulfonylbenzamide;
with methyl 2-methyl-4-isopropoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-methyl-4-isopropoxy-5-methylsulfonylbenzamide;
m.p. 185.degree.-188.degree.;
with methyl 2-methyl-4-tert-butoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-methyl-4-tert-butoxy-5-methylsulfonylbenzamide;
m.p. 205.degree.-207.degree.;
with methyl 2-methyl-4-butoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-methyl-4-butoxy-5-methylenesulfonylbenzamide;
with methyl 2-methyl-4-(2-butoxy)-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-methyl-4-(2-butoxy)-5-methylsulfonylbenzamide;
with methyl 2-methyl-4-cyclopentoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-methyl-4-cyclopentoxy-5-methylsulfonylbenzamide;
m.p. 238.degree.-241.degree.;
with methyl 2-methyl-4-(2-pentoxy)-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-methyl-4-(2-pentoxy)-5-methylsulfonylbenzamide;
with methyl 2-methyl-4-(3-pentoxy)-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-methyl-4-(3-pentoxy)-5-methylsulfonylbenzamide;
with methyl 2-methyl-4-cyclohexyloxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-methyl-4-cyclohexyloxy-5-methylsulfonylbenzamide;
m.p. 224.degree.-226.degree.;
with methyl 2-methyl-4-cyclopropoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-methyl-4-cyclopropoxy-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-methoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-methoxy-5-methylsulfonylbenzamide;
m.p. 192.degree.-195.degree.;
with methyl 2-ethyl-4-isopropoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-isopropoxy-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-propoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-propoxy-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-butoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-butoxy-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-(2-butoxy)-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-(2-butoxy)-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-tert-butoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-methyl-4-tert-butoxy-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-pentoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-pentoxy-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-(2-pentoxy)-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-(2-pentoxy)-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-(3-pentoxy)-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-(3-pentoxy)-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-cyclopropoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-cyclopropoxy-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-cyclopentoxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-cyclopentoxy-5-methylsulfonylbenzamide;
with methyl 2-ethyl-4-cyclohexyloxy-5-methylsulfonylbenzoate gives
N-diaminomethylene-2-ethyl-4-cyclohexyloxy-5-methylsulfonylbenzamide.
EXAMPLE 2
3.0 g of
N-diaminomethylene-2-ethyl-4-fluoro-5-methytsulfonylbenzamide
(obtainable by reaction of methyl
2-ethyl-4-fluoro-5-methylsulfonylbenzoate with guanidine), and 1.5
g of sodium methoxide are boiled in 25 ml of methanol for 16 hours.
Customary working up gives
N-diaminomethylene-2-ethyl-4-methoxy-5-methylsulfonylbenzamide,
m.p. 192.degree.-195.degree..
Analogously, reaction of sodium methoxide
with N-diaminomethylene-2-methyl-4-chloro-5-methylsulfonylbenzamide
gives
N-diaminomethylene-2-methyl-4-methoxy-5-methylsulfonylbenzamide,
m.p. 189.degree.-190.degree.;
EXAMPLE 3
700 mg of
N-diaminomethylene-2-ethyl-4-methoxy-methylsulfonylbenzamide
(obtainable according to Ex. 2) are suspended in 50 ml of water and
treated with 1.8 mi of 1N HCl with stirring. After filtration and
lyophilization,
N-diaminomethylene-2-ethyl-4-methoxy-5-methylsulfonylbenzamide
hydrochloride, m.p. 217.degree.-220.degree., is obtained.
Analogously, the free base gives
N-diaminomethylene-2-methyl-4-ethoxy-5-methylsulfonylbenzamide,hydrochlorid
e, m.p. 218.degree.-219.degree.;
N-diaminomethylene-2-methyl-4-isopropoxy-methylsulfonylbenzamide,
hydrochloride, m.p. 216.degree.-220.degree.;
N-diaminomethylene-2-methyl-4-cyclopentoxy-5-methylsulfonylbenzamide,
hydrochloride, m.p. >250.degree.;
N-diaminomethylene-2-methyl-4-cyclohexyloxy-5-methylsulfonylbenzamide,
hydrochloride, m.p. 185.degree.-187.degree.;
N-diaminomethylene-2-methyl-4-benzyloxy-5-methylsulfonyl-benzamide,hydrochl
oride, amorphous.
N-diaminomethylene-2-methyl-4-methoxy-5-methylsulfonylbenzamide,
hydrochloride, amorphous.
EXAMPLE 4
1.8 g of 2-methyl-4-phenoxy-5-methylsulfonylbenzoic acid
(obtainable by reaction of
2-methyl-4-chloro-5-methylsulfonylbenzoic acid with sodium
phenoxide at 180.degree.) are boiled for three hours together with
25 ml of SOCl.sub.2. The clear solution is concentrated and the
residue is dissolved in 20 ml of ethylene glycol dimethyl ether.
This reaction mixture is slowly added at room temperature to 2.5 g
of guanidine, dissolved in 30 ml of ethylene glycol dimethyl ether,
and the mixture is subsequently stirred for three hours. The
solution is then concentrated to one half, treated with 50 ml of
water, acidified and worked up in the customary manner.
N-Diaminomethylene-2-methyl-4-phenoxy-5-methylsulfonylbenzamide,
m.p. 248.degree.-250.degree., is obtained.
After suspending the base in 50 ml of water and treating it with
1.8 ml of 1N HCl with stirring,
N-di-aminomethylene-2-methyl-4-phenoxy-5-methylsulfonylbenzamide
hydrochloride, m.p. >250.degree., is obtained following
filtration and lyophilization.
EXAMPLE 5
Analogously to Example 4, reaction of
2-methyl-4-(2-chlorophenoxy)-5-methylsulfonylbenzoic acid
(obtainable by reaction of
2-methyl-4-chloro-5-methylsulfonylbenzoic acid with sodium
2-chlorophenoxide at 180.degree.) with SOCl.sub.2 and subsequently
with guanidine gives
N-diaminomethylene-2-methyl-4-(2-chlorophenoxy)-5-methylsulfonylbenzamide,
m.p. 188.degree.-191.degree..
Analogously,
2-methyl-4-(3-chlorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(3-chlorophenoxy)-5-methylsulfonylbenzamide,
m.p. 205.degree.-207.degree.;
2-methyl-4-(4-chlorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(4-chlorophenoxy)-5-methylsulfonylbenzamide,
m.p. 219.degree.-221.degree.;
2-methyl-4-(2,4-dichlorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(2,4-dichlorophenoxy)-5-methylsulfonylbenzam
ide;
2-methyl-4-(2-fluorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(2-fluorophenoxy)-5-methylsulfonylbenzamide;
2-methyl-4-(3-fluorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(3-fluorophenoxy)-5-methylsulfonylbenzamide;
2-methyl-4-(4-fluorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(4-fluorophenoxy)-5-methylsulfonylbenzamide;
2-methyl-4-(2,4-difluorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(2,4-difluorophenoxy)-5-methylsulfonylbenzam
ide;
2-methyl-4-benzyloxy-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-benzyloxy-5-methylsulfonylbenzamide,
m.p. 212.degree.-217.degree.;
2-methyl-4-(3-methoxyphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(3-methoxyphenoxy)-5-methylsulfonylbenzamide
;
2-methyl-4-(4-methoxyphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(4-methoxyphenoxy)-5-methylsulfonylbenzamide
;
2-methyl-4-(2,4-dimethoxyphenoxy)-5-methylsulfonylbenzoic acid
gives
N-diaminomethylene-2-methyl-4-(2,4-dimethoxyphenoxy)-5-methylsulfonylbenza
mide;
2-methyl-4-(2-methoxyphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(2-methoxyphenoxy)-5-methylsulfonylbenzamide
;
2-methyl-4-(3-trifluoromethylphenoxy)-5-methylsulfonylbenzoic acid
gives
N-diaminomethylene-2-methyl-4-(3-trifluoromethylphenoxy)-5-methylsulfonylb
enzamide;
2-methyl-4-(4-trifluoromethylphenoxy)-5-methylsulfonylbenzoic acid
gives
N-diaminomethylene-2-methyl-4-(4-trifluoromethylphenoxy)-5-methylsulfonylb
enzamide;
2-methyl-4-(2-trifluoromethylphenoxy)-5-methylsulfonylbenzoic acid
gives
N-diaminomethytene-2-methyl-4-(2-trifluoromethylphenoxy)-5-methylsulfonylb
enzamide;
2-methyl-4-(3-methylphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(3-methylphenoxy)-5-methylsulfonylbenzamide;
2-methyl-4-(4-methylphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(4-methylphenoxy)-5-methylsulfonylbenzamide;
2-methyl-4-(2,4-dimethylphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(2,4-dimethylphenoxy)-5-methylsulfonylbenzam
ide;
2-methyl-4-(2-methylphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-methyl-4-(2-methylphenoxy)-5-methylsulfonylbenzamide.
EXAMPLE 6
Analogously to Example 4, reaction of
2-ethyl-4-(2-chlorophenoxy)-5-methylsulfonylbenzoic acid
(obtainable by reaction of 2-ethyl-4-chloro-5-methylsulfonylbenzoic
acid with sodium 2-chlorophenoxide at 180.degree.) with SOCl.sub.2
and subsequently with guanidine gives
N-diaminomethylene-2-ethyl-4-(2-chlorophenoxy)-5-methylsulfonylbenzamide.
Analogously,
2-ethyl-4-phenoxy-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-phenoxy-5-methylsulfonylbenzamide;
2-ethyl-4-(3-chlorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(3-chlorophenoxy)-5-methylsulfonylbenzamide;
2-ethyl-4-(4-chlorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(4-chlorophenoxy)-5-methylsulfonylbenzamide;
2-ethyl-4-(2,4-dichlorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(2,4-dichlorophenoxy)-5-methylsulfonylbenzami
de;
2-ethyl-4-(2-fluorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(2-fluorophenoxy)-5-methylsulfonylbenzamide;
2-ethyl-4-(3-fluorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(3-fluorophenoxy)-5-methylsulfonylbenzamide;
2-ethyl-4-(4-fluorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(4-fluorophenoxy)-5-methylsulfonylbenzamide;
2-ethyl-4-(2,4-difluorophenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(2,4-difluorophenoxy)-5-methylsulfonylbenzami
de;
2-ethyl-4-benzyloxy-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-benzyloxy-5-methylsulfonylbenzamide;
2-ethyl-4-(3-methoxyphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(3-methoxyphenoxy)-5-methylsulfonylbenzamide;
2-ethyl-4-(4-methoxyphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(4-methoxyphenoxy)-5-methylsulfonylbenzamide;
2-ethyl-4-(2,4-dimethoxyphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(2,4-dimethoxyphenoxy)-5-methylsulfonylbenzam
ide;
2-ethyl-4-(2-methoxyphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(2-methoxyphenoxy)-5-methylsulfonylbenzamide;
2-ethyl-4-(3-trifluoromethylphenoxy)-5-methylsulfonylbenzoic acid
gives
N-diaminomethylene-2-ethyl-4-(3-trifluoromethylphenoxy)-5-methylsulfonylbe
nzamide;
2-ethyl-4-(4-trifluoromethylphenoxy)-5-methylsulfonylbenzoic acid
gives
N-diaminomethylene-2-ethyl-4-(4-trifluoromethylphenoxy)-5-methylsulfonylbe
nzamide;
2-ethyl-4-(2-trifluoromethylphenoxy)-5-methylsulfonylbenzoic acid
gives
N-diaminomethylene-2-ethyl-4-(2-trifluoromethylphenoxy)-5-methylsulfonylbe
nzamide;
2-ethyl-4-(3-methylphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(3-methylphenoxy)-5-methylsulfonylbenzamide;
2-ethyl-4-(4-methylphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(4-methylphenoxy)-5-methylsulfonylbenzamide;
2-ethyl-4-(2,4-dimethylphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(2,4-dimethylphenoxy)-5-methylsulfonylbenzami
de;
2-ethyl-4-(2-methylphenoxy)-5-methylsulfonylbenzoic acid gives
N-diaminomethylene-2-ethyl-4-(2-methylphenoxy)-5-methylsulfonylbenzamide.
EXAMPLE 7
600 mg of
N-diaminomethylene-2-methyl-4-methoxy-5-methylsulfonylbenzamide
(obtainable according to Ex. 2) are boiled for 3 hours in 80 ml of
pyridine together with 1 g of pyridine hydrochloride. The mixture
is cooled and evaporated, and the residue is worked up in the
customary manner to give
N-diaminomethylene-2-methyl-4-hydroxy-5-methylsulfonylbenzamide,
m.p. >260.degree..
EXAMPLE 8
1.1 g of
N-diaminomethylene-2-ethyl-4-benzyloxy-5-methylsulfonylbenzamide
(obtainable according to Ex. 6) are dissolved in 30 ml of toluene
and treated at room temperature for one hour with hydrogen gas (p=1
atm) under the catalytic action of 150 mg of Pd-carbon (Pd content
1%). The reaction mixture is then filtered, and customary working
up gives
N-diaminomethylene-2-ethyl-4-hyrdoxy-5-methylsulfonylbenzamide.
The following examples relate to pharmaceutical preparations:
EXAMPLE 9
Analogously to Example 3 by reaction of 1N methanesulfonate
solution with a
N-diaminomethylene-2-methyl-4-R-5-methylsulfonyl-benzamide the
following methanesulfonates are obtained (R=substituent in
4-position as subsequently given):
N-diaminomethylene-2-methyl-4-ethoxy-5-methylsulfonyl-benzamide,
methanesulfonate;
N-diaminomethylene-2-methyl-4-isopropoxy-5-methylsulfonyl-benzamide,
methanesulfonate;
N-diaminomethylene-2-methyl-4-cyclopentoxy-5-methylsulfonyl-benzamide,
methanesulfonate;
N-diaminomethylene-2-methyl-4-cycloheyloxy-5-methylsulfonyl-benzamide,
methanesulfonate;
N-diaminomethylene-2-methyl-4-benzyloxy-5-methylsulfonyl-benzamide,
methanesulfonate;
N-diaminomethylene-2-methyl-4-phenoxy-5-methylsulfonyl-benzamide,
methanesulfonate, m.p. 260.degree.-262.degree.;
N-diaminomethylene-2-methyl-4-tert.-butoxy-5-methylsulfonyl-benzamide,
methanesulfonate, m.p. 164.degree.-167.degree.;
N-diaminomethylene-2-methyl-4-(3-chlorphenoxy)-5-methylsulfonyl-benzamide,
methanesulfonate, m.p. >144.degree.;
N-diaminomethylene-2-methyl-4-hydroxy-5-methylsulfonyl-benzamide,
methanesulfonate;
N-diaminomethylene-2-methyl-4-(4-chlorphenoxy)-5-methylsulfonyl-benzamide,
methanesulfonate, m.p. >260.degree.;
N-diaminomethylene-2-methyl-4-(2-chlorphenoxy)-5-methylsulfonyl-benzamide,
methanesulfonate, m.p. 217.degree.-219.degree.;
EXAMPLE 10
Analogously to Example 1, reaction of methyl
2-methyl-4-(3-propen-1-yl)-5-methylsulfonyl-benzoate with guanidine
gives
N-diaminomethylene-2-methyl-4-(3-propen-1-yl)-5-methylsulfonyl-benzamide,
m.p. 207.degree.-209.degree..
The relating methanesulfonate is obtained analogously to Example 9,
m.p. 187.degree.-189.degree..
EXAMPLE A
Injection Vials
A solution of 100 g of an active compound of the formula I and 5 g
of disodium hydrogen phosphate are adjusted to pH 6.5 in 3 l of
double-distilled water using 2N hydrochloric acid, sterilized by
filtration, filled into injection vials, lyophilized under sterile
conditions and aseptically sealed. Each injection vial contains 5
mg of active compound.
EXAMPLE B
Suppositories
A mixture of 20 g of an active compound of the formula I is melted
with 100 g of soya lecithin and 1400 g of cocoa butter, poured into
molds and allowed to cool. Each suppository contains 20 mg of
active compound.
EXAMPLE C
Solution
A solution of 1 g of an active compound of the formula I, 9.38 g of
NaH.sub.2 PO.sub.4.2 H.sub.2 O, 28.48 g of Na.sub.2 HPO.sub.4.12
H.sub.2 O and 0.1 g of benzalkonium chloride is prepared in 940 ml
of double-distilled water. The solution is adjusted to pH 6.8, made
up to 1 l and sterilized by irradiation. This solution can be used
in the form of eye drops.
EXAMPLE D
Ointment
500 mg of an active compound of the formula I are mixed with 99.5 g
of petroleum jelly under aseptic conditions.
EXAMPLE E
Tablets
A mixture of 1 kg of active compound of the formula I, 4 kg of
lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of
magnesium stearate is compressed to give tablets in a customary
manner such that each tablet contains 10 mg of active compound.
EXAMPLE F
Coated Tablets
Analogously to Example E, tablets are pressed which are then coated
in a customary manner with a coating of sucrose, potato starch,
talc, tragacanth and colorant.
EXAMPLE G
Capsules
2 kg of active compound of the formula I are filled into hard
gelatin capsules in the customary manner such that each capsule
contains 20 mg of the active compound.
EXAMPLE H
Ampoules
A solution of 1 kg of active compound of the formula I in 60 l of
double-distilled water is sterile-filtered, filled into ampoules,
lyophilized under sterile conditions and sterile-sealed. Each
ampoule contains 10 mg of active compound.
The preceding examples can be repeated with similar success by
substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
From the foregoing description, One skilled in the art can easily
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *